The roles of acidifiers in solid dispersions and physical mixtures

Abstract

The roles of acidifiers in polyvinylpyrrolidone-based solid dispersions and physical mixtures were originally investigated on dissolution rate of drug, acidifier release, structural crystallinity and micro-environmental pH. A poorly water-soluble and weakly basic isradipine was used as a model drug. The solid dispersion and physical mixtures were prepared with drug and polyvinylpyrrolidone without or with pH modifiers using the solvent evaporation method and then compressed into tablet. The dissolution rate of drug from solid dispersions containing acidifiers were more pronounced when compared to physical mixtures. The dissolution rate of isradipine from solid dispersion was ranked by acidifiers in a decreasing order: fumaric acid, citric acid, glycolic acid and malic acid. In contrast, the acidifiers in physical mixtures had no significant difference in drug dissolution rate. It was attributed by the rank of acidifiers leading to the decrease of micro-environmental pH and slower release rate of acidifier as well as the maintenance of structural amorphousness. The selection of acidifiers with optimal micro-environmental pH, retarded release rate and maintaining structural amorphousness of drug could maximize the dissolution rate of weakly basic drug in solid dispersion.

Introduction

Solubilizations of poorly water-soluble drugs have gained much interest in the pharmaceutical industry (Riis et al., 2007, Usui et al., 1998). In general, poorly water-soluble drugs are weakly acidic or basic drug in nature, and show pH-dependent solubility. For this reason, modulating the pH in dosage forms using pH modifiers can modify the release rate of several pH-dependent and ionizable drugs (Doherty and York, 1989, Siepe et al., 2006a, Siepe et al., 2006b, Tran et al., 2008). For example, a weakly basic drug is deprotonated and unionized in intestinal fluids, decreasing pH-dependent drug dissolution (Guthmann et al., 2008, Li and Zhao, 2007). The pH modifiers that lower micro-environmental pH (pH_M) of the dosage forms can enhance drug dissolution under basic conditions. Succinic acid/potassium dihydrogen phosphate blends are used as pH modifiers to improve verapamil hydrochloride release from Eudragit RL and RS matrix tablets (Gohel et al., 2003). Previously, Streubel et al. (2000) also used fumaric acid to obtain pH independent release of verapamil hydrochloride from matrix tablets. In addition, Siepe et al., 2006a, Siepe et al., 2006b designed fumaric acid-loaded hydrophilic HPMC matrix tablets to control pH_M.

In general, solid dispersion (SD) is a molecular mixture of drug in various hydrophilic carriers used to enhance drug dissolution by changing drug crystallinity to an amorphous form and reducing particle size for better wettability (Heo et al., 2005, Tran et al., 2009). Dissolution-modulating mechanisms of incorporating alkalizers in non-nanoemulsifying or nanoemulsifying “crystalline” SD were also investigated using pH-dependent model drugs (Tran et al., 2008, Tran et al., 2009). Drug is present in a crystalline form but pH modifiers could readily reduce drug crystallinity and modulate pH_M, resulting in enhanced drug. Despite the wide uses of pH modifiers in dosage forms, the roles of acidifiers in SD or physical mixture (PM) on dissolution rate of drug and acidifier, pH_M and structural crystallinity are not clearly investigated. Release rate of incorporating pH modifiers in SD and PM are regarded as a key factor to maintain pH_M, leading to enhanced dissolution rate of drug.

Here, we incorporated four acidifiers in polyvinylpyrrolidone (PVP)-based SD and PM and then compressed in tablet. The PM was also prepared for comparison. A weakly basic poorly water-soluble isradipine (IDP) was chosen as a model drug. IDP is a calcium antagonist for treating hypertension (Chrysant and Cohen, 1997) and known to be poorly water-soluble in aqueous solution (less than 10 μg/mL) due to the weakly basic amine group (Verger et al., 1998). Then, dissolution rate of drug, release of acidifier, structural crystallinity of drug and pH_M of tablet were investigated. The four acidifiers include fumaric acid, citric acid, glycolic acid and malic acid. At first, IDP solubility in 1.0% acidifier solution was measured. The release rate of acidifiers and the surface and inner pH_M of the tablet were potentiometrically measured as a function of time using a surface pH electrode. We also investigated intermolecular hydrogen-bonding interactions of IDP with acidifiers within SD using a differential scanning calorimeter (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR). Finally, dissolution rate of drug was measured in enzyme-free simulated intestinal fluid (pH 6.8).